Antibodies to .beta.-amyloids or their derivatives and use thereof

• US 5,750,349 A
• Filed: 09/15/1994
• Issued: 05/12/1998
• Est. Priority Date: 01/25/1993
• Status: Expired due to Term

• Current Assignee: Takeda Pharmaceutical Company Limited
• Original Assignee: Takeda Chemical Industries, Ltd. (Takeda Pharmaceutical Company Limited)
• Inventors: Odaka, Asano, Kitada, Chieko, Suzuki, Nobuhiro
• Primary Examiner(s): Hutzell, Paula K.
• Assistant Examiner(s): DUFFY, PATRICIA ANN
• Application Number:
  US08/302,808
• Time in Patent Office: 1,335 Days
• Field of Search: 435/7.1, 435/7.92, 435/7.94, 435/70.21, 435/240.27, 435/240.26, 435/7.95, 435/331, 435/326, 436/811, 530/387.9, 530/388.1, 530/389.1
• US Class Current: 435/7.1
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: C07K 14/4711 Alzheimer's disease; Amyloid plaque core protein
• CPC Class Codes: C07K 16/18 against material from animals or humans

Abstract

According to this invention, antibodies which are useful and novel in that they have binding specificity to β-amyloids or derivatives thereof, namely recognize the N-terminal, the C-terminal or central portions of the β-amyloids, respectively, were obtained. By combining these antibodies, determination methods by which the β-amyloids could be determined sensitively and specifically are provided. These determination methods are useful for diagnosis of diseases to which the β-amyloids or their derivatives are related (for example, Alzheimer'"'"'s disease), and the antibodies of this invention are useful for the development of preventive-therapeutic compositions for Alzheimer'"'"'s disease.

Claims

1. An antibody specifically reactive to a peptide on the C-terminal side of a β

-amyloid comprising the amino acid sequence of SEQ ID NO;

1, SEQ ID NO;

2, SEQ ID NO;

3, SEQ ID NO;

4, SEQ ID NO;

5 or SEQ ID NO;

6 or a derivative thereof which is a peptide lacking 1 to 17 amino acid residues from the N-terminal portion of the said β

-amyloid, a peptide in which L-aspartic acid of the said β

-amyloid is isomerized to L-isoaspartic acid, D-isoaspartic acid or D-aspartic acid, and a peptide in which the N-terminal portion of the said β

-amyloid has pyroglutamic acid, and, in which said antibody does not recognize a peptide comprising the amino acid sequence of SEQ ID NO;

7.

2. The antibody as claimed in claim 1, which is BA-27a in which said antibody does not recognize a peptide comprising the amino acid sequence of SEQ ID NO:

8 and a peptide comprising the amino acid sequence of SEQ ID NO;

9.

3. The antibody as claimed in claim 1, in which the said antibody recognizes a peptide comprising the amino acid sequence of SEQ ID NO:

8, but does not recognize a peptide comprising the amino acid sequence of SEQ ID NO;

9.

4. The antibody as claimed in claim 1, in which said antibody does not recognize a peptide comprising the amino acid sequence of SEQ ID NO:

8, but recognizes a peptide comprising the amino acid sequence of SEQ IS NO;

9.

5. The antibody as claimed in claim 1, 2, 3 or 4, in which said antibody is a monoclonal antibody.

6. A hybridoma cell producing the monoclonal antibody as claimed in claim 5.

7. A method for determining the presence of a β

-amyloid or a derivative thereof in a test solution which comprises contacting said test solution with an antibody as claimed in claim 1, and determining whether said antibody binds a β

-amyloid or a derivative thereof in said test solution, wherein said β

-amyloid comprises the amino acid sequence of SEQ ID NO;

1, SEQ ID NO;

2, SEQ ID NO;

3, SEQ ID NO;

4, SEQ ID NO;

5 or SEQ ID NO;

6 and said derivative thereof is a peptide lacking 1 to 17 amino acid residues from the N-terminal portion of the said β

-amyloid, a peptide in which L-aspartic acid of the said β

-amyloid is isomerized to L-isoaspartic acid, D-isoaspartic acid or D-aspartic acid, and a peptide in which the N-terminal portion of the said P-amyloid has pyroglutamic acid.

8. A method for determining the presence of a β

-amyloid or a derivative thereof in a test solution which comprises contacting said test solution with an antibody as claimed in claim 1 and

(i) a monoclonal antibody designated by BAN-052a secreted by hybridoma NIBH accession number FERM BP-4138 and specifically reactive to a peptide on the N-terminal side of a P-amyloid or a derivative thereof, in which said antibody recognizes a peptide comprising the amino acid sequence of SEQ ID NO;

7 and/or a peptide comprising the amino acid sequence of SEQ ID NO;

10, or

(ii) a monoclonal antibody designated by BAN-50a secreted by hybridoma NIBH accession number FERM BP-4163 and specifically reactive to a peptide on the N-terminal side of a p-amyloid or a derivative thereof, in which said antibody recognizes a peptide comprising the amino acid sequence of SEQ ID NO;

7 and/or a peptide comprising the amino acid sequence of SEQ ID NO;

10, and determining whether said antibodies bind β

-amyloid or a derivative thereof in said solution, wherein said β

-amyloid comprises the amino acid sequence of SEQ ID NO;

1, SEQ ID NO;

2, SEQ ID NO;

3, SEQ ID NO;

4, SEQ ID NO;

5 or SEQ ID NO;

6 and said derivative thereof is a peptide lacking 1 to 17 amino acid residues from the N-terminal portion of the said P-amyloid, a peptide in which L-aspartic acid of the said β

-amyloid is isomerized to L-isoaspartic acid, D-isoaspartic acid or D-aspartic acid, or a peptide in which the N-terminal portion of the said β

-amyloid has pyroglutamic acid.

9. A diagnostic composition for Alzheimer'"'"'s disease which comprises

(i) an antibody of claim 1,

(ii) a monoclonal antibody designated by BAN-052a secreted by hybridoma NIBH accession number FERM BP-4138 and specifically reactive to a peptide on the N-terminal side of a β

-amyloid or a derivative thereof, in which said antibody recognizes a peptide comprising the amino acid sequence of SEQ ID NO;

7 and/or a peptide comprising the amino acid sequence of SEQ ID NO;

10,

(iii) a monoclonal antibody designated by BAN-50a secreted by hybridoma NIBH accession number FERM BP-4163 and specifically reactive to a peptide on the N-terminal side of a β

-amyloid or a derivative thereof, in which said antibody recognizes a peptide comprising the amino acid sequence of SEQ ID NO;

7 and/or a peptide comprising the amino acid sequence of SEQ ID NO;

10, or

(iv) an antibody specifically reactive to a p-amyloid or a derivative thereof, in which said antibody does not recognize a peptide comprising the amino acid sequence of SEQ ID NO;

7, but recognizes a peptide comprising the amino acid sequence of SEQ ID NO;

12,

and a labeling substance, wherein said β

-amyloid comprises the amino acid sequence of SEQ ID NO;

1, SEQ ID NO;

2, SEQ ID NO;

3, SEQ ID NO;

4, SEQ ID NO;

5 or SEQ ID NO;

6 and said derivative thereof is a peptide lacking 1 to 17 amino acid residues from the N-terminal portion of the said β

-amyloid, a peptide in which L-aspartic acid of the said β

-amyloid is isomerized to L-isoaspartic acid, D-isoaspartic acid or D-aspartic acid, and a peptide in which the N-terminal portion of the said β

-amyloid has pyroglutamic acid.